Despite a comparatively low toxic threshold, bupivacaine is the most common local anesthetic in children (1,2). Bupivacaine consists of two enantiomers, dexbupivacaine (R[+]-bupivacaine) and levobupivacaine (S[−]-bupivacaine). Studies in animals have shown that the excess toxicity of bupivacaine is caused by dexbupivacaine (3–8). Although there may be subtle pharmacodynamic differences among levobupivacaine, dexbupivacaine, and racemic bupivacaine at large doses (8,9), at normal clinical concentrations, the local anesthetic properties of the three drugs are equivalent in both animals (3) and humans (10,11).
We conducted a randomized, double-blinded, placebo-controlled study of the efficacy and side effects of levobupivacaine for ilioinguinal/iliohypogastric (IIIH) nerve block in children.
We obtained approval by our institutional review board and informed, written consent from each patient’s parent(s). ASA physical status I or II children aged 6 mo to 12 yr undergoing outpatient inguinal herniorrhaphy were eligible for the study. Children were excluded if they had neurologic, neuromuscular, psychiatric, seizure, or blood clotting disorders or a known allergy to amide local anesthetics or any drug in the protocol.
Patients received acetaminophen 15 mg/kg PO 30 min before surgery; patients <1 yr of age received atropine 0.01 mg/kg IM. One patient in each group received midazolam 0.5 mg/kg PO for anxiolysis. Anesthesia was induced with sevoflurane in N2O/O2 (2:1) and was maintained with halothane in N2O/O2 (2:1) via a mask or laryngeal mask airway with spontaneous ventilation. All patients received metoclopramide 0.2 mg/kg iv as prophylaxis for emesis. No other drugs, including opioids, other analgesics, or local anesthetics other than the study drug, were given during surgery. Patients were randomized to receive either an IIIH block with 0.25 mL/kg 0.5% levobupivacaine (Chiroscience Limited, Cambridge, UK) per side operated (Group LB) or no block (Group NB) at the conclusion of surgery; all IIIH blocks were performed by one of the authors (JBG) who was not involved in the subsequent care or evaluation of the patients. An adhesive bandage was applied to the block site(s) on all patients to blind postoperative observers.
Patients were evaluated for 2 h after surgery; time to awakening, emesis, vital signs (every 30 min), and a subjective evaluation of block quality (0 = poor, 1 = fair, 2 = good, 3 = excellent) were recorded. The Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) (12) was recorded every 5 min for 30 min and every 15 min for the remainder of the observation period. All scores were made by one of three dedicated study nurses with high interrater concordance on the CHEOPS (κW = 0.88 for Nurse 1 versus Nurse 2; κW = 0.77 for Nurse 1 versus Nurse 3). Patients with a CHEOPS score ≥10 received up to three doses (at 5-min intervals) of morphine 0.05 mg/kg IV, followed by one dose of ketorolac 1 mg/kg IV; patients could also receive rescue analgesics on request. Patients who received all four doses of rescue analgesics without satisfactory pain relief were withdrawn from the study, and additional analgesics were administered. Parents were phoned at 48–72 h after surgery to review recovery at home.
Assuming that IIIH block would be successful in 70% of patients and that rescue analgesics would be needed in 80% of patients not receiving a block, with α = 0.05 and β = 0.2, 20 patients were required in each group. Parametric data were analyzed by using Student’s t-test. Ordinal data are presented as median and were analyzed by using the Mann-Whitney U-test. Categorical data are presented as absolute numbers or percentages and were analyzed by using Fisher’s exact test or χ2 as appropriate. Time to rescue analgesic administration was analyzed by using Kaplan-Meier life tables and the Mantel-Haenszel χ statistic.
Thirty-nine children were studied. One patient was not randomized because no observer was available for the 2-h study period. Three patients were randomized to Group NB but were excluded from the study before entering the observation period; one received local infiltration by the surgeon and the other two underwent surgery more extensive than originally planned. The remaining 35 patients were randomized, and all completed the 2-hour observation period. Demographic data are presented in Table 1.
Compared with Group LB, patients in Group NB awakened sooner (24 ± 16 vs 36 ± 22 min; P = 0.077) and had lower block quality scores (1 vs 2; P = 0.083), but the differences did not achieve statistical significance. There was no difference in the overall rate of rescue analgesic administration between Group NB and Group LB (11 of 15 vs 9 of 20; P = 0.18); however, the mean number of rescue doses was higher in Group NB than in Group LB (1.4 ± 1.2 vs 0.7 ± 1.0; P = 0.058). No patient in either group required more than four rescue analgesic doses. Group NB required rescue analgesics sooner than Group LB (Figure 1). CHEOPS scores in Group NB were higher than those in Group LB 15, 25, 30, and 60 min after surgery (Figure 2). The time-weighted mean CHEOPS score was higher in Group NB than in Group LB (6.9 ± 0.7 vs 6.4 ± 0.6; P = 0.03).
There were no differences in heart rate or blood pressure between the two groups during the observation period. There was no difference in the incidence of adverse events (most often nausea, emesis, or pain) between Groups NB and LB. Two patients in Group LB experienced ipsilateral femoral nerve block, which resolved by the morning after surgery. Delayed urination that resolved without treatment was seen in two patients in Group LB. One patient in Group NB returned to the operating room for repair of wound dehiscence.
Levobupivacaine was effective for IIIH block in children undergoing herniorrhaphy, as demonstrated by a longer time to rescue analgesic administration, fewer rescue analgesic doses, and lower CHEOPS scores compared with patients not receiving a block. All adverse events seen were expected with herniorrhaphy (pain, nausea/emesis) or IIIH block, regardless of the local anesthetic used (ipsilateral femoral nerve block, delayed micturition).
We were unable to demonstrate a difference in the need for analgesic rescue between the groups. This was due to a higher than anticipated requirement for rescue analgesics in Group LB (45% vs 30% predicted); the rate of rescue analgesic administration in Group NB was as expected (73% vs 80% predicted). There are several reasons why this may have been so. Poor technique may have led to incomplete IIIH block. Because many of the behaviors scored on the CHEOPS are also seen in children experiencing emergence delirium, some patients may have received rescue analgesics for delirium, not pain. The observation that most patients in Group LB (16 of 20) required, at most, one rescue analgesic dose is compatible with both incomplete block and delirium.
The absence of a long-acting local anesthetic with a pediatric indication led to our decision to perform a placebo-controlled study. Ethical concerns regarding a placebo-controlled analgesic study were ameliorated by the administration of acetaminophen to all patients and the ready availability of rescue analgesics. This format also allowed observations regarding the natural history of pain and analgesic requirements in children after herniorrhaphy. More than 25% of patients in Group NB did not require any additional analgesics after surgery.
In a variety of animal models, levobupivacaine has been shown to have lower toxicity than dexbupivacaine or bupivacaine racemate (3–6). The decreased cardiac toxicity of levobupivacaine compared with dexbupivacaine has particular significance to pediatric anesthesia. Because of differences in epidural anatomy, children require more local anesthetic than adults for epidural blockade; volumes of 1 ml/kg 0.25% bupivacaine (2.5 mg/kg) are often used for caudal blockade in children (2). Infants have a relative deficiency of acid α1-glycoprotein, a principal binding protein for bupivacaine, and have an increased plasma free-fraction of bupivacaine (13); it is unknown whether this increase in bupivacaine free-fraction is enantiomerically specific. Most regional anesthetics in children are performed with the patient anesthetized, which reduces the utility of test dosing in detecting intravascular injection. Thus, because of differences in local anesthetic requirements, plasma protein binding, and anesthetic practice, children—especially infants—may be at increased risk of local anesthetic toxicity. Although morbidity due to local anesthetic toxicity is rare in children, as demonstrated by a recent series of 24,000 children having local or regional anesthesia, of whom only 4 had either convulsions or cardiac dysrhythmias (14), the availability of a long-acting local anesthetic with a higher toxic threshold than that of bupivacaine racemate is desirable.
Levobupivacaine was effective for IIIH block in children undergoing outpatient herniorrhaphy, as demonstrated by a longer time to rescue analgesic administration, a reduced requirement for rescue analgesics, lower CHEOPS scores 15, 25, 30, and 60 minutes after surgery, and lower time-weighted mean CHEOPS scores. The adverse events seen were those expected for children undergoing herniorrhaphy and IIIH block. Although additional evaluation in more subjects is clearly required before firm conclusions can be reached, levobupivacaine has the potential to serve as a long-acting, less toxic alternative to bupivacaine racemate in children.
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